Project Abstract Memory recall in the waking state provides the basis for mental exploration of past and possible future actions to guide behavior. As severe memory impairments pervade widespread neuropsychiatric disorders, investigation of the unknown neural mechanisms that underlie the brain's memory system is crucial for developing targeted clinical interventions. The recall of recent memory is dependent on the intact hippocampus (HPC) and surrounding rhinal cortices, and is hypothesized to rely on a specific mechanism: spatially tuned `place' cells in the HPC index spatially-associated representations, such that activating a particular sequence of place cells can reanimate a trace of the original episodic activity patterns across the cortex. These spatially coherent sequences of place cells have been observed in the HPC, and in particular occur as discrete bursts of activity within network oscillations, called sharp wave ripples (SWRs). Although mounting evidence suggests that SWR's are ideally suited to propagate mnemonic information, critical questions remain open that are necessary to further establish their mechanistic role in memory. First, in order to determine whether these events orchestrate the reactivation of a coherent memory trace throughout the brain, confirmation that the representational content of awake SWR-replay is faithfully coordinated across the hippocampal-cortical circuit must be established. Second, it is unknown to what extent awake reactivation of mnemonic sequences from the HPC contributes to two important memory processes: imagination of potential future action, or the induction of neural plasticity to consolidate episodic associations. In order to directly address these critical questions, we propose to investigate the precise nature of awake SWR-related activity between the HPC and its primary target for spatial information, the medial entorhinal cortex (MEC). We hypothesize that awake SWR-replay directly drives hippocampal-cortical coordinated reactivation to guide both decision-making and memory consolidation. We will test this hypothesis with multi-site electrophysiological recording of neural activity in HPC and MEC of rats learning a spatial memory task (Aims 1, 2, and 3). We will also use a bipolar microstimulation electrode in the ventral hippocampal commissure to selectively disrupt SWRs and establish their causal role in hippocampal-cortical activity patterns and decision-making (Aim 3). Our specific aims are: Aim 1: To test the hypothesis that the MEC activity corresponds to that of hippocampal SWR-replay. Aim 2: To test the hypothesis that SWR-related activity in MEC is predictive of behavioral performance. Aim 3: To test the hypothesis that awake SWRs prime sequence association for memory consolidation. Testing these hypotheses would be a critical advance in linking neural activity to memory functions, the potential impact of which is underscored by documented impairments of sequence reactivation in models of neuropsychiatric disorders such as schizophrenia and dementia. As critical components of the brain's memory system, the HPC and MEC are priorities for scientific inquiry and promising targets for clinical intervention.